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Trial registered on ANZCTR


Registration number
ACTRN12611001206910
Ethics application status
Approved
Date submitted
19/11/2011
Date registered
23/11/2011
Date last updated
7/05/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naive Adults with Chronic Hepatitis B (CHB) Infection
Scientific title
A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naive Adults with Chronic Hepatitis B (CHB) Infection
Secondary ID [1] 273412 0
EudraCT Number: 2011-004586-33
Universal Trial Number (UTN)
N/A
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B (CHB) Infection 279205 0
Condition category
Condition code
Infection 279410 279410 0 0
Sexually transmitted infections

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
4 different doses of GS-7340 (8-mg, 25-mg, 40-mg, and 120-mg) will be studied. Subjects will only be assigned to one of the doses for the entire duration of the study period of 28 days. These tablets will be administered orally once daily under fasted conditions for 28 days.
Intervention code [1] 283749 0
Treatment: Drugs
Comparator / control treatment
Tenofovir disoproxil fumarate (TDF) 300-mg will be the active control for this study. This will be one of the five treatment groups that a subject can be assigned to. TDF tablet will be administered orally once daily under fasted conditions for 28 days.
Control group
Active

Outcomes
Primary outcome [1] 285982 0
Primary Outcome: time-weighted average change from Baseline through Week 4 (DAVG4) in serum HBV DNA (log10 IU/mL) for GS-7340 8-, 25-, 40- and 120-mg
Timepoint [1] 285982 0
Baseline through Week 4 on Days 1, 2, 5, 8, 10, 15, 19, 22, and 29.
Secondary outcome [1] 294894 0
Time-weighted average change from Baseline through Week 4 (DAVG4) in serum HBV DNA (log10 IU/mL) for tenofovir disoproxil fumarate (TDF) 300-mg
Timepoint [1] 294894 0
Baseline through Week 4 on Days 1, 2, 5, 8, 10, 15, 19, 22, and 29.
Secondary outcome [2] 294964 0
Time-weighted average change from Baseline through Week 1, 2, 3 in serum HBV DNA (log10 IU/mL) for all treatment groups
Timepoint [2] 294964 0
Baseline through Week 1 to 3 on Days 1, 2, 3, 5, 6, 10, 15, and 19
Secondary outcome [3] 294965 0
Change from Baseline in HBV DNA (log10 IU/mL) at Day 14 and Day 29
Timepoint [3] 294965 0
Day 14 and Day 29
Secondary outcome [4] 294966 0
Subject viral decay slope of GS-7340. HBV DNA will be measured with COBAS TaqMan HBV Test For Use with the High Pure System
Timepoint [4] 294966 0
Baseline through Week 4 on Days 1, 2, 5, 8, 10, 15, 19, 22, and 29.
Secondary outcome [5] 294967 0
Incidence of adverse events and graded laboratory abnormalities, which will be assessed clinically as well as through hematology and serum chemistry panel. Some possible adverse events include: headaches, nausea, and flatulence.
Timepoint [5] 294967 0
Screening through Week 4 on Days 1, 2, 5, 8, 10, 15, 19, 22, and 29 as well as follow up Days 15 and 30
Secondary outcome [6] 294968 0
PK parameters of plasma GS-7340 and tenofovir following single and multiple doses of GS-7340
Timepoint [6] 294968 0
Baseline through Week 4 on Days 1, 2, 5, 8, 10, 15, 19, 22, and 29.

Eligibility
Key inclusion criteria
1. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
2. Must be between 18 and 65 years of age, inclusive on the date of the screening visit
3. Must have Screening plasma HBV DNA greater than or equal to 2x103 IU/mL
4. Eligible subjects must have chronic hepatitis B infection documented to be at least 6 months in duration (e.g. by positive serum HBsAg)
5. Have estimated creatinine clearance (CLCr) > 70 mL/min (using the Cockcroft-Gault method) {2202} based on serum creatinine and actual body weight as measured at the Screening evaluation, ie,:
Male: (140 – age in years) x (wt in kg) = CLCr (mL/min)
72 x (serum creatinine in mg/dL)
Female: (140 – age in years) x (wt in kg) x 0.85 = CLCr (mL/min) 72 x (serum creatinine in mg/dL)
6. A female subject is eligible to enter the study if she is:
Not pregnant or nursing
Of non-childbearing potential (i.e., women who have had a hysterectomy, have both ovaries removed or medically documented ovarian failure), or are postmenopausal – women > 50 years of age with permanent cessation of previously occurring menses greater than or equal to 12 months as a result of ovarian failure with documentation of hormonal deficiency
* Of childbearing potential (i.e., women who have not had a hysterectomy, both ovaries removed or no medically documented ovarian failure). Women greater than or equal to 50 years of age with amenorrhea will be considered to be of childbearing potential. These women must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to randomization and agree to 1 of the following:
* Complete abstinence from intercourse from the date of Screening until 30 days following the last dose of study drugs
OR
* Consistent and correct use of 1 of the following protocol recommended methods of birth control, in addition to a male partner who correctly uses a condom from the date of Screening until 30 days after the last dose of study drugs
- implants of levonorgestrel
- injectable progesterone
- any intrauterine device (IUD) with a documented failure rate of less than 1% per year
- oral contraceptives (either combined or progesterone only), subjects should have been using this method for 3 months prior to initiating study drugs
- female barrier method: cervical cap or diaphragm
- vaginal ring
- transdermal contraceptive patch
- tubal sterilization
- vasectomy in male subject or male partner
7. All male subjects must agree to consistently and correctly use a condom while their female partner agrees to use 1 of the appropriate medically accepted methods of birth control listed above from the date of Screening until 30 days after their last dose of study drugs
8. Male subjects must agree to refrain from sperm donation for at least 60 days after the last dose
9. Subjects must refrain from blood donation from baseline/Day 1 through completion of the study and continuing for at least 30 days from date of last dose of study drug
10. Subjects must, in the opinion of the Investigator, be in good general health based upon medical history, physical examination (including vital signs), and Screening laboratory evaluations (hematology, chemistry, and urinalysis must fall within the central laboratory’s reference normal ranges unless the results have been determined by the Investigator to have no clinical significance):
- ALT (SGPT) greater than or equal to 10 X ULN at Screening
- Adequate hematologic function (absolute neutrophil count > or = 1,500/mm3 or > or = 1,000/mm3 if considered a physiologic variant in a subject of African decent; hemoglobin > or = 10.0 g/dL)
11. Must be willing and able to comply with all study requirements
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or lactating subjects
2. Receipt of anti-HBV nucleoside/nucleotide therapy. Subjects who have failed prior Interferon treatment, greater than 6 months prior to screening, are permitted to participate in the study
3. Known co-infection with HIV, HCV or HDV
4. Presence of autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, psoriasis of greater than mild severity)
5. Have a history of liver disease other than Hepatitis B
6. Have a history of Gilbert’s Disease
7. Known or suspected cirrhosis
8. Evidence of hepatocellular carcinoma (eg, fetoprotein > 50 ng/mL or as indicated by recent ultrasound or other standard of care measure)
9. Any sign of decompensated liver disease, including prothrombin time greater than or equal to 1.5 x ULN, platelets < 100,000/mm3 or albumin < 3.5 g/dL at Screening OR current or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy or variceal hemorrhage)
10. Have a history or family history of Long QT Syndrome, Wolfe-Parkinson-White Syndrome, or have a family history of sudden cardiac death or unexplained death in an otherwise healthy individual between the ages of 1 and 40 years
11. Presence or history of cardiovascular disease, cardiomyopathy, and/or cardiac conduction abnormalities
12. Have clinically relevant electrolyte abnormalities
13. History of medical or surgical treatment that permanently alters the gastric condition (eg, gastrectomy)
14. Have previously participated in an investigational trial involving administration of any investigational compound within 30 days prior to the study dosing
15. Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance
16. Subjects having a positive screen for amphetamines, barbiturates, cocaine, or methadone at either the Screening or baseline/day 1 visit are not permitted to participate in the study. Subjects having a positive screen for barbiturates, benzodiazepines, and/or opiates at the Screening evaluation may be re tested at baseline/Day 1. Subjects on stable methadone maintenance may be considered after discussion with the medical monitor
17. Have a history of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
18. Have consumed grapefruit, grapefruit juice, pomegranate juice or Seville orange juice within 7 days prior to Day 1
19. Known hypersensitivity to the study drugs, the metabolites or formulation excipients
20. Are unable to comply with study requirements
21. Have a history of bleeding diathesis
22. Significant bone disease, (eg, osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses), or multiple bone fractures
23. Believed by the study Investigator, to be inappropriate for study participation for any reason including any not otherwise listed. For example: renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (eg, diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
After Screening procedures, eligible subjects will be randomized via IWRS into treatment groups 1:1:1:1:1 to receive either open-label GS-7340 8-, 25-, 40-, or 120-mg (3 x 40mg), or open-label TDF 300-mg for 28 days.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random treatment assignment is made by IWRS to treatment groups: open-label GS-7340 8-, 25-, 40-, 120-mg or open-label TDF 300-mg. Randomization is stratified by subjects’ HBeAg status (negative or positive). The randomization schedule is generated by SAS (Registered Trademark) [Copyright (c) 2002-2003 by SAS Institute Inc., Cary, NC, USA].
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/01/2012
Actual
21/03/2012
Date of last participant enrolment
Anticipated
Actual
4/03/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 4747 0
3181
Recruitment postcode(s) [2] 4746 0
6009
Recruitment outside Australia
Country [1] 3960 0
United Kingdom
State/province [1] 3960 0
London
Country [2] 3961 0
United Kingdom
State/province [2] 3961 0
Birmingham
Country [3] 3962 0
United Kingdom
State/province [3] 3962 0
Nottingham
Country [4] 3963 0
Canada
State/province [4] 3963 0
British Columbia
Country [5] 3964 0
Canada
State/province [5] 3964 0
Ontario
Country [6] 3965 0
Canada
State/province [6] 3965 0
Quebec
Country [7] 3966 0
Canada
State/province [7] 3966 0
Alberta
Country [8] 3967 0
New Zealand
State/province [8] 3967 0
Auckland

Funding & Sponsors
Funding source category [1] 284230 0
Commercial sector/Industry
Name [1] 284230 0
Gilead Sciences, Inc
Country [1] 284230 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc
Address
333 Lakeside Drive
Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 269185 0
None
Name [1] 269185 0
Address [1] 269185 0
Country [1] 269185 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286193 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 286193 0
229 Greenhill Road
Dulwich, SA 5065
Ethics committee country [1] 286193 0
Australia
Date submitted for ethics approval [1] 286193 0
12/10/2011
Approval date [1] 286193 0
21/03/2012
Ethics approval number [1] 286193 0

Summary
Brief summary
This is a randomized, open-label, active-controlled study whose primary objective is to evaluate the safety and efficacy of several doses of GS-7340. This study will evaluate the safety, viral kinetics, and antiviral activity of each of four doses of GS-7340 over 28 days of therapy. In addition, the study will evaluate the antiviral activity of an optimal dose of GS-7340 versus TDF 300-mg over 28 days of therapy.
Approximately 50 eligible subjects with chronic HBV infection who are naïve to anti-HBV treatment will be randomized 1:1:1:1:1 to receive treatment with GS-7340 8-, 25-, 40-, or 120-mg or TDF 300-mg orally once daily.
Subjects may be HBeAg+ or HBeAg-. Enrollment will be stratified by HBeAg status with approximately a 1:1 distribution resulting in approximately 25 HBeAg+ and 25 HBeAg- subjects.
All subjects must be followed for safety for 30 days after the 28-day treatment.
Optional blood samples may be obtained for exploratory biomarker and pharmacogenomic discovery research at any time during the study or at a separate post study visit, if necessary. Subjects who agree to have blood drawn for pharmacogenomic research will sign a separate informed consent form.
Trial website
Trial related presentations / publications
The plan is to publish and present at an appropriate scientific conference when data are available
Public notes

Contacts
Principal investigator
Name 33410 0
Dr Edward Gane
Address 33410 0
Gastroenterology Dept, Bldg 15
Hospital Road, Private Bag 93311
Otahuhu
Auckland New Zealand 1042
Country 33410 0
New Zealand
Phone 33410 0
+64 2154 8371
Fax 33410 0
Email 33410 0
edgane@adhb.govt.nz;fayem@adhb.govt.nz
Contact person for public queries
Name 16657 0
Desiree Varela
Address 16657 0
333 Lakeside Drive
Foster City, CA 94404
Country 16657 0
United States of America
Phone 16657 0
+1 (650) 372-4417
Fax 16657 0
Email 16657 0
Desiree.Varela@gilead.com
Contact person for scientific queries
Name 7585 0
John Flaherty
Address 7585 0
333 Lakeside Drive
Foster City, CA 94404
Country 7585 0
United States of America
Phone 7585 0
1 (650) 522-5592
Fax 7585 0
Email 7585 0
John.Flaherty@gilead.com

No information has been provided regarding IPD availability


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